Method for producing alkylsulfinylbenzamides and 1,2-benzisothiazol-3-ones

ABSTRACT

A method for producing an alkylthiobenzamide by carrying out a reaction of a halobenzamide with an alkanethiol in the presence of a base in a heterogeneous solvent; a method for producing an alkylsulfinylbenzamide by carrying out a reaction of an alkylthiobenzamide with a halogen in a heterogeneous solvent; a method for producing an alkylsulfinylbenzamide by carrying out a reaction of a halobenzamide with an alkanethiol in the presence of a base in a heterogeneous solvent and a subsequent reaction with a halogen; and a method for producing a 1,2-benzisothiazol-3-one by carrying out a reaction of a 2-(alkylthio)benzamide with a halogenating agent.

This application is a continuation divisional of application Ser. No.08/342,038, filed on Nov. 17, 1994, now U.S. Pat. No. 5,508,416, theentire contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for producingalkylsulfinylbenzamides and 1,2-benzisothiazol-3-ones. Moreparticularly, the present invention relates to a method for producingalkylsulfinylbenzamides which are useful as intermediates for1,2-benzisothiazol-3-ones, etc. and a method for producing1,2-benzisothiazol-3-ones directly from 2-(alkylthio)benzamides.1,2-benzisothiazol-3-ones are compounds useful as antibacterial agentsand antifungal agents.

2. Discussion of the Related Art

The following methods are known for producing alkyl sulfinylbenzamides.

(A) Bull. Chem. Soc. Jpn., 55, 1183-1187 (1982) ##STR1## (B) TetrahedronLett., 33, 153-156 (1992) ##STR2##

These conventional methods, however, are not advantageous for industrialuse for various reasons. Specifically, Method (A) has problems instability and production of its starting material, 2-(methylthio)benzoylchloride. Also, periodic acid, which is expensive and dangerous, is usedin this method.

Method (B) has a problem in obtaining the starting material, because nomethods have been disclosed for producing the starting material,N-phenyl-2-(methylthio)benzamide. In addition, this method also uses adangerous substance, m-chloroperbenzoic acid (m-CPBA).

There are also several methods known for producing1,2-benzisothiazol-3-ones, including the following ones.

(C) Bull. Chem. Soc. Jpn., 55, 1183-1187 (1982) ##STR3##

In the above method, 2-(methylthio)benzamide is produced from2-(methylthio)benzoylchloride; oxidized with periodic acid to2-(methylsulfinyl)benzamide; and cyclized in the presence of thionylchloride to yield a 1,2-benzisothiazol-3-one.

(D) Ger. Offen. 3500577 (1986) ##STR4##

In the above method, a desired 1,2-benzisothiazol-3-one may be obtainedusing thiosalicylic acid as a starting material and sodium hydroxide asa cycling agent in the final process.

(E) J. Org. Chem. 40(14), 2029-2032 (1975) ##STR5##

In the above method, a desired 1,2-benzisothiazol-3-one is obtainedusing thiosalicylic acid as a starting material and a strong base in thefinal cyclization process.

However, these conventional methods have the following drawbacks:

In Method (C), a desired 1,2-benzisothiazol-3-one is synthesized in twosteps, that is, 2-(methylthio)benzamide is oxidized to2-(methylsulfinyl)benzamide, which is then cyclized in the presence ofthionyl chloride. This method needs use of periodic acid, a dangerousand expensive substance.

Method (D) requires expensive thiosalicylic acid as the startingmaterial, a strong base for cyclization, and involves many reactionsteps. Therefore, this method is not satisfactory for industrial use.

Also, Method (E) uses expensive thiosalicylic acid as the startingmaterial and a strong base for cyclization, and involves many reactionsteps, and, therefore, is not suitable for industrial use.

As stated above, all known methods require more than one reaction stepsto produce 1,2-benzisothiazol-3-ones from 2-(alkylthio)benzamides, andare not satisfactory for production on an industrial scale.

SUMMARY OF THE INVENTION

Accordingly, in view of the above problems, an object of the presentinvention is to provide a method for producing alkylsulfinylbenzamidesindustrially advantageously without using expensive and hazardoussubstances as the starting materials.

It is another object of the present invention to provide a method forproducing alkylthiobenzamides which are useful as intermediates for theproduction of the alkylsulfinylbenzamides.

It is also an object of the present invention to provide a method forproducing 1,2-benzisothiazol-3-ones, important compounds asantibacterial agents, antifungal agents, etc., in high yield, by a safeand short process without using any expensive and dangerous substances.

In order to achieve the above objects, the present inventors firstinvestigated to provide an easy and economically advantageous method forproducing alkylsulfinylbenzamides. As a result, the inventors found thatan alkylsulfinylbenzamide represented by the general formula (IV) caneasily be obtained in high yield by the reaction of a halobenzamiderepresented by general formula (I) with an alkanethiol represented bythe general formula (II) in a heterogeneous solvent system in thepresence of a base to yield an intermediary alkylthiobenzamiderepresented by the general formula (III), followed by a further reactionof this alkylthiobenzamide with a halogen in a heterogeneous solvent.##STR6## wherein X represents Cl or Br, R¹ represents a hydrogen atom,or an alkyl group having 1 to 4 carbon atoms, an aryl group, or anaralkyl group, and R² represents an alkyl group having 1 to 4 carbonatoms.

In order to achieve the object of the present invention, the inventorsfurther investigated to develop an industrially advantageous method forproducing 1,2-benzisothiazol-3-ones. As a result, the inventorsunexpectedly found that a 1,2-benzisothiazol-3-one represented by thegeneral formula (VI) can directly be obtained by a reaction between a2-(alkylthio)benzamide represented by the general formula (V) and ahalogenating agent. Unlike conventional methods, the cyclization can beachieved in one reaction step without via an intermediaryalkylsulfinylbenzamide in this method. ##STR7## wherein R³ represents ahydrogen atom, or a linear or branched alkyl group having 1 to 12 carbonatoms, a cycloalkyl group, an aryl group, or an aralkyl group; R⁴represents an alkyl group having 1 to 4 carbon atoms; R⁵ represents ahydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxygroup having 1 to 4 carbon atoms, a nitro group, a carboxyl group or anester thereof, or a halogen atom.

The present invention has been completed by conducting further researchbased upon the above findings.

The present invention is concerned with the following:

(1) A method for producing an alkylthiobenzamide represented by thegeneral formula (III), comprising carrying out a reaction of ahalobenzamide represented by the following general formula (I): ##STR8##wherein X represents Cl or Br, and R¹ represents a hydrogen atom, or analkyl group having 1 to 4 carbon atoms, an aryl group, or an aralkylgroup,

with an alkanethiol represented by the following general formula (II):

    R.sup.2 SH                                                 (II)

wherein R² represents an alkyl group having 1 to 4 carbon atoms, in thepresence of a base in a heterogeneous solvent,

to give an alkylthiobenzamide represented by the following generalformula (III): ##STR9## wherein R¹ and R² are defined as above; (2) Amethod for producing an alkylsulfinylbenzamide represented by thefollowing general formula (IV), comprising carrying out a reaction of analkylthiobenzamide represented by the following general formula (III):##STR10## wherein R¹ and R² are defined as above, with a halogen in aheterogeneous solvent, to give an alkylsulfinylbenzamide represented bythe following general formula (IV): ##STR11## wherein R¹ and R² aredefined as above; (3) A method for producing an alkylsulfinylbenzamiderepresented by the general formula (IV), comprising carrying out areaction of a halobenzamide represented by the following general formula(I): ##STR12## wherein X and R¹ are defined as above, with analkanethiol represented by the following general formula (II):

    R.sup.2 SH                                                 (II)

wherein R² is defined as above,

in the presence of a base in a heterogeneous solvent; and then adding ahalogen to the above reaction mixture for a further reaction to give analkylsulfinylbenzamide represented by the following general formula(IV): ##STR13## wherein R¹ and R² are defined as above; and (4) A methodfor producing a 1,2-benzisothiazol-3-one represented by the generalformula (VI), comprising carrying out a reaction of a2-(alkylthio)benzamide represented by the following general formula (V):##STR14## wherein R³ represents a hydrogen atom, or a linear or branchedalkyl group having 1 to 12 carbon atoms, a cycloalkyl group, an arylgroup, or an aralkyl group; R⁴ represents an alkyl group having 1 to 4carbon atoms; R⁵ represents a hydrogen atom, an alkyl group having 1 to4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a nitrogroup, a carboxyl group or an ester thereof, or a halogen atom,

with a halogenating agent to give a 1,2-benzisothiazol-3-one representedby the following general formula (VI): ##STR15## wherein R³ and R⁵ aredefined as above.

According to the present invention, an alkylsulfinylbenzamide canreadily be synthesized from a halobenzamide, the starting materialeasily available for industrial use, via an intermediaryalkylthiobenzamide, in a one-pot process. The method of the presentinvention is industrially and economically advantageous because itallows to produce easily an alkylsulfinylbenzamide in high yield withless discharge of aqueous waste and without the use of expensive andhazardous substances.

Also, according to the present invention, 1,2-benzisothiazol-3-ones suchas 2-phenyl-1,2-benzisothiazol-3-one and 1,2-benzisothiazol-3-one,important substances as antibacterial and antifungal agents, can beproduced from alkylthiobenzamides in high yield in one-step and undersafe reaction conditions without use of expensive and hazardoussubstances.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be explained in detail below by explainingmethods for producing alkylsulfinylbenzamides and methods for producing1,2-benzisothiazole-3-ones separately.

A! Method for producing alkylsulfinylbenzamides

The method for producing alkylsulfinylbenzamides of the presentinvention is characterized in that a desired alkylsulfinylbenzamide caneasily be produced in high yield under relatively mild conditions bynovel reaction, wherein a halobenzamide, which is available at a lowcost for industrial use, is converted to an intermediaryalkylthiobenzamide.

1) Method for producing alkylthiobenzamides

The method for producing alkylthiobenzamides (III) of the presentinvention is a novelmethod characterized by a reaction of ahalobenzamide represented by the general formula (I) with an alkanethiolrepresented by the general formula (II) in the presence of a base in aheterogeneous solvent system.

In the above general formulas (I), (II) and (III), R¹ represents ahydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl groupor an aralkyl group, and R² represents an alkyl group having 1 to 4carbon atoms. The alkyl groups may be linear or branched. Examples ofsuch alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl and tert-butyl groups. Examples of the aryl groupsinclude phenyl, 4-tolyl and 1-naphthyl groups. Examples of the aralkylgroups include benzyl and phenethyl groups.

The halobenzamides represented by the general formula (I) used in thepresent invention are not particularly limited, and examples thereofinclude 2-chlorobenzamide, N-ethyl-2-chlorobenzamide,N-phenyl-2-chlorobenzamide, N-4-tolyl-2-chlorobenzamide,N-benzyl-2-chlorobenzamide, 2-bromobenzamide, N-ethyl-2-bromobenzamide,N-phenyl-2-bromobenzamide, N-4-tolyl-2-bromobenzamide,N-benzyl-2-bromobenzamide, 4-chlorobenzamide, N-ethyl-4-chlorobenzamide,N-phenyl-4-chlorobenzamide, N-4-tolyl-4-chlorobenzamide,N-benzyl-4-chlorobenzamide, 4-bromobenzamide, N-ethyl-4-bromobenzamide,N-phenyl-4-bromobenzamide, N-4-tolyl-4-bromobenzamide, andN-benzyl-4-bromobenzamide.

Alkanethiols represented by the general formula (II) are exemplified bymethanethiol, ethanethiol, 1-propanethiol, 1-butanethiol and2-butanethiol. The amount of alkanethiol used is normally 0.8 to 3.0times, preferably 1.0 to 2.0 times the molar quantity of halobenzamideused. If the amount of alkanethiol used is less than 0.8 times,unchanged halobenzamide increases. Even though the amount of alkanethiolexceeds 3.0 times, additional effect cannot be expected, and, therefore,it is economically disadvantageous.

Bases which can be used in the reaction of a halobenzamide with analkanethiol include alkali metal hydroxides, such as sodium hydroxideand potassium hydroxide; alkali metal carbonates, such as sodiumcarbonate and potassium carbonate; and metal alcoholates, such as sodiummethylate and sodium ethylate. From the economic viewpoint, sodiumhydroxide is preferably used. The amount of base used is normally 0.8 to3.5 times, preferably 1.0 to 2.5 times the molar quantity ofhalobenzamide used. If the amount of base used is less than 0.8 times,unchanged halobenzamide increases. Even if the amount of base usedexceeds 3.5 times, additional effect cannot be expected, and, therefore,it is economically disadvantageous.

The method of the present invention for producing an alkylthiobenzamiderepresented by the general formula (III) is characterized in that thereaction is carried out in a heterogeneous solvent system in thepresence of water. The reaction of the starting materials, ahalobenzamide with an alkanethiol, is carried out in a two-phase solventsystem, because a halobenzamide is insoluble in water. In these cases, aphase-transfer catalyst is preferably added to the reaction system topromote the reaction. Phase-transfer catalysts which can be used forthis purpose include quaternary ammonium salts, such asbenzyltriethylammonium bromide, benzyltrimethylammonium chloride,hexadecyltriethylammonium bromide, hexadecyltrimethylammonium chloride,dodecyltrimethylammonium chloride, octyltriethylammonium bromide,tetra-n-butylammonium bromide, tetra-n-butylammonium chloride,tetraethylammonium chloride and trioctylmethylammonium chloride;quaternary phosphonium salts, such as hexadecyltriethylphosphoniumbromide, hexadecyltributylphosphonium chloride, tetra-n-butylphosphoniumbromide, tetra-n-butylphosphonium chloride, trioctylethylphosphoniumbromide and tetraphenylphosphonium bromide; and crown ethers, such as18-crown-6, dibenzo-18-crown-6 and dicyclohexyl-18-crown-6. From theeconomic viewpoint, quaternary ammonium salts, such astetra-n-butylammonium bromide and tetra-n-butylammonium chloride, arepreferably used.

The amount of phase-transfer catalyst used is normally 0.005 to 0.5times, preferably 0.01 to 0.2 times the weight of halobenzamide. Whenthe amount of phase-transfer catalyst used is less than 0.005 times theweight of halobenzamide, adequate catalytic effect cannot be obtained.Even if the amount of phase-transfer catalyst used exceeds 0.5 times theweight of halobenzamide used, additional expected effect cannot beobtained, and, therefore, it is economically disadvantageous.

In order to facilitate the reaction and the separation of the reactionmixture, the reaction solvent used in the present invention is normallya heterogeneous solvent consisting of water and 1 to 10 parts by weightof a water-insoluble organic solvent based on 1 part by weight of water.Water-insoluble organic solvents are not particularly limited andinclude hydrocarbons, such as n-hexane, n-heptane, cyclohexane,methylcyclohexane, benzene, toluene and xylene; and halogenatedhydrocarbons, such as methylene chloride, 1,2-dichloroethane andchlorobenzene. The amount of heterogeneous solvent used is normally 1 to30 times the weight of halobenzamide.

The reaction temperature for the present invention is normally 0° to150° C., preferably 20° to 120° C. Reaction temperature higher than 150°C. causes side reactions. On the other hand, the reaction rateunfavorably lowers to an impractical level when the reaction temperatureis less than 0° C. The reaction time varies with the reactiontemperature and the types of phase-transfer catalyst and reactionsolvent and cannot be generalized, but it is normally in the rangebetween 1 and 40 hours.

After completion of the reaction, an alkylthiobenzamide can be isolatedand purified from the separated organic solvent layer by an ordinaryprocedure, such as crystallization. Since the water layer separatedcontains a phase-transfer catalyst, it can successively and repeatedlybe used in subsequent reactions. Therefore, almost no aqueous waste isdischarged out of the reaction system. The separated organic solventlayer containing an alkylthiobenzamide can also directly be used in thenext reaction.

2) Method for producing alkylsulfinylbenzamides

An alkylsulfinylbenzamide represented by the general formula (IV) can beproduced by the reaction of the thus-obtained alkylthiobenzamiderepresented by the general formula (III) with a halogen in aheterogeneous solvent system. R¹ and R² in the general formula (IV) havethe same definitions as those of R¹ and R² in the general formula (III).

The halogens used here include chlorine and bromine. In view of thereaction selectivity, bromine is preferred. The amount of halogen isnormally 0.8 to 2.0 times, preferably 1.0 to 1.3 times the molarquantity of alkylthiobenzamide. When the amount of halogen used is lessthan 0.8 times the molar quantity of alkylthiobenzamide, the amount ofunchanged alkylthiobenzamide increases. On the other hand, the amount ofhalogen used exceeds 2.0 times, side reactions occur and lower theyield.

Hydrogen halides, by-products of the reaction between analkylthiobenzamide and a halogen, can be neutralized in the reactionsystem. The bases used for this purpose include alkali metal hydroxides,such as sodium hydroxide and potassium hydroxide; alkali metalcarbonates, such as sodium carbonate, potassium carbonate, sodiumbicarbonate and potassium bicarbonate; metal alcoholates, such as sodiummethylate and sodium ethylate; and organic amines, such as triethylamineand pyridine. From the economic viewpoint, sodium hydroxide or sodiumbicarbonate is preferably used.

In order to facilitate the reaction and the isolation of the reactionproduct, the solvent used in the reaction between an alkylthiobenzamideand a halogen is normally a heterogeneous solvent system consisting ofwater and 1 to 10 parts by weight of a water-insoluble organic solventbased on 1 part by weight of water. Water-insoluble organic solvents arenot particularly limited, and include hydrocarbons, such as n-hexane,n-heptane, cyclohexane, methylcyclohexane, benzene, toluene and xylene;and halogenated hydrocarbons, such as methylene chloride,1,2-dichloroethane and chlorobenzene. The amount of heterogeneoussolvent used is normally 1 to 30 times the weight of alkylthiobenzamide.

The reaction temperature for the reaction between an alkylthiobenzamideand a halogen is normally -10° to 100° C., preferably 0 to 50° C.Reaction temperature higher than 100° C. causes side reactions. On theother hand, the reaction rate unfavorably lowers to an impractical levelwhen the reaction temperature is less than -10° C. The reaction timevaries with the reaction temperature and reaction solvent, and it isnormally in the range between 1 and 40 hours.

In the present invention, starting with a halobenzamide represented bythe general formula (I) and an alkanethiol having the general formula(II), an alkylthiobenzamide represented by the general formula (III) isfirst synthesized. This intermediary compound isolated is made to reactwith a halogen in the next step to yield a desiredalkylsulfinylbenzamide. In the present invention, besides the above2-step method, a one-pot reaction can also be used for producingalkylsulfinylbenzamides. In the one-pot reaction, a halobenzamide, analkanethiol and a halogen are used as the starting materials. In thiscase, the organic solvent layer containing an intermediaryalkylthiobenzamide is separated from the water layer by removal of thelatter and made to react with a halogen without isolating thealkylthiobenzamide. When an alkylsulfinylbenzamide is to be obtained bythe one-pot reaction, it is preferable to use a heterogeneous solventsystem consisting of toluene and water. The isolation ofalkylsulfinylbenzamide from the reaction mixture obtained by thetwo-step method or by the one-pot reaction can normally be carried outby crystallization or recrystallization from the separated organicsolvent layer.

The thus-obtained alkylsulfinylbenzamide is represented by the generalformula (IV). The alkylsulfinylbenzamides are exemplified by2-(alkylsulfinyl)benzamides, such as 2-(methylsulfinyl)benzamide,2-(ethylsulfinyl)benzamide, 2-(n-propylsulfinyl)benzamide,2-(isopropylsulfinyl)benzamide, 2-(n-butylsulfinyl)benzamide,2-(isobutylsulfinyl)benzamide, 2-(sec-butylsulfinyl)benzamide,2-(tert-butylsulfinyl)benzamide, N-ethyl-2-(methylsulfinyl)benzamide,N-phenyl-2-(methylsulfinyl)benzamide,N-4-tolyl-2-(methylsulfinyl)benzamide,N-benzyl-2-(methylsulfinyl)benzamide,N-ethyl-2-(ethylsulfinyl)benzamide, N-phenyl-2-(ethylsulfinyl)benzamide,N-4-tolyl-2-(ethylsulfinyl)benzamide andN-benzyl-2-(ethylsulfinyl)benzamide, and 4-(alkylsulfinyl)benzamides,such as 4-(methylsulfinyl)benzamide, 4-(ethylsulfinyl)benzamide,N-ethyl-4-(methylsulfinyl)benzamide,N-phenyl-4-(methylsulfinyl)benzamide,N-4-tolyl-4-(methylsulfinyl)benzamide, andN-benzyl-4-(methylsulfinyl)benzamide.

B! Method for producing 1,2-benzisothiazol-3-ones

The method for producing a 1,2-benzisothiazol-3-one of the presentinvention is characterized in that a 2-(alkylthio)benzamide (V) isemployed as the starting material readily available for industrial use,and cyclizes in only one step to directly produce a1,2-benzisothiazol-3-one (VI), unlike conventional methods which involvetwo-step processes via an intermediary alkylsulfinylbenzamide. Anotherfeature of this method lies in that a 1,2-benzisothiazol-3-one can beproduced safely under relatively mild conditions without using dangerousand expensive substances.

The same definitions for R³ and R⁵ are applied to both the formulas (V)and (VI). Specifically, R³ represents a hydrogen atom, a linear orbranched alkyl group having 1 to 12 carbon atoms, a cycloalkyl group, anaryl group or an aralkyl group.

The alkyl groups for R³ are exemplified by methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-decyl and n-dodecyl groups. The cycloalkyl groupsfor R³ are exemplified by cyclopentyl and cyclohexyl. The aryl groupsfor R³ are exemplified by phenyl, 4-tolyl, 4-methoxyphenyl,4-chlorophenyl and 1-naphthyl groups. The aralkyl group for R³ isexemplified by benzyl and phenethyl.

Preferred examples of R³ include a hydrogen atom, and methyl, ethyl,isopropyl, n-butyl, tert-butyl, n-dodecyl, cyclohexyl, phenyl, 4-tolyl,4-methoxyphenyl, 4-chlorophenyl, 1-naphthyl and benzyl groups, with agreater preference given to a hydrogen atom and a phenyl group.

R⁴ in the general formula (V) represents an alkyl group having 1 to 4carbon atoms. The alkyl groups for R⁴ are exemplified by methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups.

Preferred examples of R⁴ include methyl, ethyl, n-propyl and tert-butylgroups, with a greater preference given to methyl and tert-butyl groups.

R⁵ in the general formulas (V) and (VI) represents a hydrogen atom, analkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4carbon atoms, a nitro group, a carboxyl group or ester thereof, or ahalogen atom. The alkyl groups for R⁵ are exemplified by methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups.Alkoxy groups for R⁵ are exemplified by methoxy, ethoxy, propoxy andbutoxy groups. Esters of carboxyl group for R⁵ are exemplified bymethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl.Halogens for R⁵ are exemplified by chlorine and bromine.

Preferred examples for R⁵ include a hydrogen atom, a n-butyl group, amethoxy group, a nitro group and a chlorine atom, with a greaterpreference given to a hydrogen atom.

The starting materials, 2-(alkylthio)benzamides represented by thegeneral formula (V) in the present invention are not particularlylimited, and examples thereof include the following:2-(methylthio)benzamide, 2-(ethylthio)benzamide,2-(tert-butylthio)benzamide, N-ethyl-2-(methylthio)benzamide,N-ethyl-2-(ethylthio)benzamide, N-isopropyl-2-(methylthio)benzamide,N-(tert-butyl)-2-(methylthio)benzamide, N-hexyl-2-(methylthio)benzamide,N-octyl-2-(methylthio)benzamide, N-decyl-2-(methylthio)benzamide,N-dodecyl-2-(methylthio)benzamide, N-cyclohexyl-2-(methylthio)benzamide,N-phenyl-2-(methylthio)benzamide, N-(4-tolyl)-2-(methylthio)benzamide,N-(4-methoxyphenyl)-2-(methylthio)benzamide,N-(4-chlorophenyl)-2-(methylthio)benzamide,N-(1-naphthyl)-2-(methylthio)benzamide,N-benzyl-2-(methylthio)benzamide, N-benzyl-2-(propylthio)benzamide,N-benzyl-2-(butylthio)benzamide,N-phenyl-3-methyl-2-(methylthio)benzamide,N-methyl-5-butyl-2-(methylthio)benzamide,N-butyl-4-methoxy-2-(methylthio)benzamide,N-phenyl-2-methylthio-3-nitrobenzamide,4-chloro-2-(methylthio)benzamide, 4-carboxy-2-(methylthio)benzamide, and4-methoxycarbonyl-2-(methylthio)benzamide.

Although a 2-(alkylthio)benzamide represented by the general formula (V)may be prepared by any methods, it can be obtained more advantageouslyby the aforementioned method for producing an alkylthiobenzamide of thepresent invention.

The method for producing a 1,2-benzisothiazol-3-one from a2-(alkylthio)benzamide of the present invention is carried out by thereaction of the 2-(alkylthio)benzamide with a halogenating agent. Thedetail of this method is hereinafter described.

Any halogenating agents may be used for this process of the presentinvention, as long as it is capable of reacting with a sulfide toproduce a sulfonium halide. Such reagents include sulfuryl halides SO₂X₂ (VII), wherein X represents Cl or Br!, such as sulfuryl chloride andsulfuryl bromide; phosphorus chlorides, such as phosphorus pentachlorideand phosphorus trichloride; and such as chlorine, bromine and iodine.Among them, sulfuryl chloride, phosphorus pentachloride, phosphorustrichloride and chlorine are preferably used.

The reaction solvents used for the halogenation process to obtain1,2-benzisothiazol-3-ones are not particularly limited as long as it isinert to the reaction. Examples of the reaction solvent includehydrocarbons, such as n-hexane, n-heptane, cyclohexane,methylcyclohexane, benzene, toluene and xylene; and halogenatedhydrocarbons, such as methylene chloride, 1,2-dichloroethane,chloroform, carbon tetrachloride, and monochlorobenzene.

Of the above-mentioned reaction solvents, toluene, xylene andmonochlorobenzene are preferred, because the entire process, i.e., fromthe synthesis of a 2-(alkylthio)benzamide represented by the generalformula (V) by a reaction between a halobenzamide represented by thefollowing general formula (VIII) and an alkanethiol represented by thefollowing general formula (IX) to the synthesis of a1,2-benzisothiazol-3-one by a reaction between the2-(alkylthio)benzamide and a halogenating agent, can be very efficientlyachieved in a one-pot: ##STR16## The conditions for the reaction betweena halobenzamide (VIII) and an alkanethiol (IX) are the same as those forthe reaction between a halobenzamide (I) and an alkanethiol (II).

The amount of solvent used is normally 1 to 30 times the weight of2-(alkylthio)benzamide used.

The reaction temperature is normally 0° to 150° C., preferably 20° to120° C. Reaction temperature higher than 150° C. causes the problems ofside reactions. On the other hand, reaction rate lowers to animpractical level when the reaction temperature is less than 0° C. Thereaction time varies with the reaction temperature and the type of andreaction solvent, and it is normally in the range between 1 and 40hours.

A desired 1,2-benzisothiazol-3-one can be isolated and purified from thethus-obtained reaction mixture by the conventional methods, i.e., bydistillation under reduced pressure when the desired1,2-benzisothiazol-3-one is liquid, or by direct crystallization orextraction and subsequent recrystallization when the desired1,2-benzisothiazol-3-one is solid. There is no limitation to thesemethods.

Examples of 1,2-benzisothiazol-3-ones represented by the general formula(VI) obtained by the method of the present invention include:

1,2-benzisothiazol-3-one,

2-ethyl-1,2-benzisothiazol-3-one,

2-isopropyl-1,2-benzisothiazol-3-one,

2-(tert-butyl)-1,2-benzisothiazol-3-one,

2-hexyl-1,2-benzisothiazolo3-one,

2-octyl-1,2-benzisothiazol-3-one,

2-decyl-1,2-benzisothiazol-3-one,

2-dodecyl-1,2-benzisothiazol-3-one,

2-cyclohexyl-1,2-benzisothiazol-3-one,

2-phenyl-1,2-benzisothiazol-3-one,

2-(4-tolyl)-1,2-benzisothiazol-3-one,

2-(4-methoxyphenyl)-1,2-benzisothiazol-3-one,

2-(4-chlorophenyl)-1,2-benzisothiazol-3-one,

2-(1-naphthyl)-1,2-benzisothiazol-3-one,

2-benzyl-1,2-benzisothiazol-3-one,

7-methyl-2-phenyl-1,2-benzisothiazol-3-one,

5-butyl-2-methyl-1,2-benzisothiazol-3-one,

2-butyl-6-methoxy-1,2-benzisothiazol-3-one,

7-nitro-2-phenyl-1,2-benzisothiazol-3-one,

6-chloro-1,2-benzisothiazol-3-one,

6-carboxy-1,2-benzisothiazol-3-one, and

6-methoxycarbonyl-1,2-benzisothiazol-3-one.

EXAMPLES

The present invention will be further described by means of thefollowing working examples and a production example, without intendingto restrict the scope of the present invention thereto.

Incidentally, the obtained product is confirmed by nuclear magneticresonance method (¹ H-NMR) and mass spectroscopy in order to determinewhether a desired product is obtained.

Production Example 1

Production of N-Phenyl-2-chlorobenzamide

To a 500 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 31.3 g (0.2 mol) of 2-chlorobenzoic acid and 180 g oftoluene are placed. To the above mixture in the flask, 25.0 g (0.21 mol)of thionyl chloride is added dropwise over 30 minutes while stirring ata temperature of from 60° to 65° C. to be allowed to react with eachother for about 30 minutes. To the above reaction mixture, a solutioncontaining 27.9 g (0.3 mol) of aniline dissolved in 100 g of toluene isdropwise added to be allowed to react with each other at a temperatureof from 70° to 75° C. for 30 minutes. After completion of the reaction,the reaction mixture is cooled to room temperature, and 70 g of a 5% byweight hydrochloric acid solution is added to the above mixture. Themixture is vigorously shaken and kept standing for separation of thetoluene layer from the aqueous layer. After separation of the toluenelayer, it is condensed to precipitate white crystals, followed byrecrystallization (in a water/methanol mixture of 3/7), to give 43.1 gof N-phenyl-2-chlorobenzamide (melting point: 116° to 117° C.). Theyield of the product against 2-chlorobenzoic acid is 93%.

Example 1

Production of N-Phenyl-2-(methylthio)benzamide

To a 500 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 46.3 g (0.2 mol) of N-phenyl-2-chlorobenzamide obtainedin Production Example 1, 100 g of toluene, and 9.3 g of an aqueoussolution of 50% by weight tetra-n-butylammonium bromide are placed.Separately, 12.0 g (0.30 mol) of sodium hydroxide and 113.7 g of waterare placed into another container under a nitrogen gas atmosphere, and14.5 g (0.30 mol) of methanethiol are added to the above mixture at roomtemperature over about 1 hour to prepare 140.2 g of sodium salt solutionof methanethiol. 140.2 g (0.3 mol) of the aqueous solution of sodiummethyl mercaptan thus prepared is added to the mixture containingN-phenyl-2-chlorobenzamide described above at 80° C. while stirring, tobe allowed to react with each other under reflux for 1 hour. Aftercompletion of the reaction, the reaction mixture is cooled to roomtemperature to precipitate white crystals, which are washed with waterand then with toluene and dried, to give 46.2 g ofN-phenyl-2-(methylthio)benzamide (melting point 148 to 149° C.). Theyield of the product against N-phenyl-2-chlorobenzamide is 95%.

Example 2

Production of N-Phenyl-2-(methylsulfinyl)benzamide

To a 1000 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 48.6 g (0.2 mol) of N-phenyl-2-(methylthio)benzamideobtained in Example 1, 300 g of toluene, and 200 g of a 10% by weightaqueous solution of potassium bicarbonate are placed. To the abovemixture in the flask, 32.0 g (0.2 mol) of bromine is added dropwisewhile stirring at a temperature of from 10° to 15° C. to be allowed toreact with each other for about 10 minutes. After completion of thereaction, the produced white crystals are filtered and thenrecrystallized from a mixture of water and ethanol (1:9) to give 48.7 gof N-phenyl-2-(methylsulfinyl)benzamide (melting point: 194° to 195°C.). The yield of the product against N-phenyl-2-(methylthio)benzamideis 94%.

Example 3

Production of N-Phenyl-2-(methylsulfinyl)benzamide from 2-ChlorobenzoicAcid by One-Pot Reaction

To a 1000 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 31.3 g (0.2 mol) of 2-chlorobenzoic acid and 300 g oftoluene-are placed, and the same procedures as in Production Example 1are carried out. To the toluene layer containing the product,N-phenyl-2-chlorobenzamide, 9.3 g of an aqueous solution of 50% byweight tetra-n-butylammonium bromide is added. To this mixture, 140.2 g(0.3 mol) of an aqueous solution of sodium methyl mercaptan prepared asin Example 1 is added and the same reaction as in Example 1 is carriedout. After completion of the reaction, the reaction mixture is separatedwhile heating, and the toluene layer is separated out. To the obtainedtoluene layer, 200 g of a 10% by weight aqueous solution of potassiumbicarbonate is added, and to this mixture, 38.4 g (0.24 mol) of bromineis added dropwise at a temperature of from 10° to 15° C. while stirringto be allowed to react with each other under the same conditions as inExample 2. As a result of conducting the entire procedure in one pot,the yield of N-phenyl-2-(methylsulfinyl)benzamide against2-chlorobenzoic acid is 81%.

Example 4

Production of 2-Phenyl-1,2-benzisothiazol-3-one

To a 500 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 48.6 g (0.2 mol) of N-phenyl-2-(methylthio)benzamideand 100 g of toluene are placed. To the above mixture in the flask, 29.7g (0.22 mol) of sulfuryl chloride is added while stirring at atemperature of from 20° to 30° C., and then the components are heatedand allowed to react with each other at a temperature of from 70° to 80°C. for 1 hour.

After completion of the reaction, the reaction mixture is cooled to roomtemperature, and the precipitated white crystals are washed withtoluene, and then dried to give 44.0 g of2-phenyl-1,2-benzisothiazol-3-one (melting point: 140° to 141° C.). Theyield of the product is 97% against N-phenyl-2-(methylthio)benzamide,which is used as the starting material of the reaction.

Example 5

Production of 1,2-Benzisothiazol-3-one

To a 500 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 33.4 g (0.2 mol) of 2-(methylthio)benzamide and 150 gof toluene are placed. To the above mixture in the flask, 28.3 g (0.21mol) of sulfuryl chloride is added while stirring at a temperature offrom 20° to 30° C., and then the components are heated and allowed toreact with each other at a temperature of from 70° to 80° C. for 1 hour.

After completion of the reaction, the reaction mixture is cooled to roomtemperature, and the precipitated white crystals are washed withtoluene, and then dried to give 29.0 g of 1,2-benzisothiazol-3-one(melting point: 157° to 158° C.). The yield of the product is 96%against 2-(methylthio)benzamide, which is used as the starting materialof the reaction.

Examples 6 to 18

Production of 1,2-Benzisothiazol-3-ones

The same procedures as in Example 4 are carried out except thatN-phenyl-2-(methylthio)benzamide is replaced with each of the2-(alkylthio)benzamides shown in Tables 1 to 3, to give a corresponding1,2-benzisothiazol-3-one. In the case where the corresponding1,2-benzisothiazol-3-one is a liquid, it is obtained by distillationunder a reduced pressure. The melting points and the yields of theproducts are also shown in Tables 1 to 3.

Example 19

Production of 2-Phenyl-1,2-benzisothiazol-3-one

The same procedures as in Example 4 are carried out except that sulfurylchloride in Example 4 is replaced with 83.4 g (0.4 mol) of phosphoruspentachloride, to give 36.7 g of 2-phenyl-1,2-benzisothiazol-3-one. Theyield of the product against N-phenyl-2-(methylthio)benzamide is 81%.

Example 20

Production of 2-Phenyl-1,2-benzisothiazol-3-one

To a 500 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 48.6 g (0.2 mol) of N-phenyl-2-(methylthio)benzamideprepared as in Example 1 and 100 g of monochlorobenzene are placed. Tothe above mixture in the flask, 18.5 g (0.26 mol) of chlorine is addedwhile stirring at a temperature of from 40° to 50° C., and then thecomponents are heated and allowed to react with each other at atemperature of from 70° to 80° C. for 1 hour.

After completion of the reaction, the reaction mixture is cooled to roomtemperature, and the precipitated white crystals are washed withmonochlorobenzene, and then dried to give 44.5 g of2-phenyl-1,2-benzisothiazol-3-one (melting point: 140° to 141° C.). Theyield of the product is 98% against N-phenyl-2-(methylthio)benzamide,which is used as the starting material of the reaction.

Example 21

Production of 1,2-Benzisothiazol-3-one

To a 500 ml four-necked flask equipped with a stirrer, a thermometer,and a condenser, 33.4 g (0.2 mol) of 2-(methylthio)benzamide and 150 gof monochlorobenzene are placed. To the above mixture in the flask, 18.5g (0.26 mol) of chlorine is added while stirring at a temperature offrom 40° to 50° C., and the components are then heated and allowed toreact with each other at a temperature of from 70° to 80° C. for 1 hour.

After completion of the reaction, the reaction mixture is cooled to roomtemperature, and the precipitated white crystals are washed withmonochlorobenzene, and then dried to give 29.3 g of1,2-benzisothiazol-3-one (melting point: 157° to 158° C.). The yield ofthe product is 97% against 2-(methylthio)benzamide, which is used as thestarting material of the reaction.

The results of Examples 4 to 21 are shown together in Tables 1 to 3.

                                      TABLE 1                                     __________________________________________________________________________    Example                                Yield*                                 No.  2-(Alkylthio)benzamides                                                                        1,2-Benzisothiazol-3-ones                                                                      (%)                                    __________________________________________________________________________    4    N-Phenyl-2-(methylthio)benzamide                                                               2-Phenyl-1,2-benzisothiazol-3-one                                                              97                                                           (melting point: 140-141° C.)                     5    2-(Methylthio)benzamide                                                                        1,2-Benzisothiazol-3-one                                                                       96                                                           (melting point: 157-158° C.)                     6    N-Ethyl-2-(ethylthio)benzamide                                                                 2-Ethyl-1,2-benzisothiazol-3-one                                                               94                                                           (boiling point: 126-127° C./2 mmHg)              7    N-Isopropyl-2-(methylthio)benzamide                                                            2-Isopropyl-1,2-benzisothiazol-3-one                                                           92                                                           (boiling point: 126-128° C./2 mmHg)              8    N-(tert-Butyl)-2-(methylthio)benzamide                                                         2-(tert-Butyl)-1,2-benzisothiazol-3-one                                                        94                                                           (melting point: 57-58° C.)                       9    N-Dodecyl-2-(methylthio)benzamide                                                              2-Dodecyl-1,2-benzisothiazol-3-one                                                             91                                                           (a waxy solid)                                          __________________________________________________________________________     Note *Yield of 1,2Benzisothiazol-3-one against 2(Alkylthio)benzamide.    

                                      TABLE 2                                     __________________________________________________________________________    Example                                     Yield*                            No.  2-(Alkylthio)benzamides                                                                          1,2-Benzisothiazol-3-ones                                                                         (%)                               __________________________________________________________________________    10   N-Cyclohexyl-2-(methylthio)benzamide                                                             2-Cyclohexyl-1,2-benzisothiazol-3-one                                                             93                                                        (melting point: 87-88° C.)                     11   N-Benzyl-2-(propylthio)benzamide                                                                 2-Benzyl-1,2-benzisothiazol-3-one                                                                 96                                                        (melting point: 87-88° C.)                     12   N-(1-Naphthyl)-2-(methylthio)benzamide                                                           2-(1-Naphthyl)-1,2-benzisothiazol-3-one                                                           94                                                        (melting point: 154-155° C.)                   13   N-(4-Tolyl)-2-(methylthio)benzamide                                                              2-(4-Tolyl)-1,2-benzisothiazol-3-one                                                              95                                                        (melting point: 136-137° C.)                   14   N-(4-Methoxyphenyl)-2-(methylthio)-                                                              2-(4-Methoxyphenyl)-1,2-benzisothiazol-3-one                                                      93                                     benzamide          (melting point: 148-149° C.)                   15   N-Methyl-5-butyl-2-(methylthio)benzamide                                                         5-Butyl-2-methyl-1,2-benzisothiazo1-3-one                                                         92                                                        (melting point: 87-88° C.)                     __________________________________________________________________________     Note *Yield of 1,2Benzisothiazol-3-one against 2(Alkylthio)benzamide.    

                                      TABLE 3                                     __________________________________________________________________________    Example                                     Yield*                            No.  2-(Alkylthio)benzamides                                                                           1,2-Benzisothiazol-3-ones                                                                        (%)                               __________________________________________________________________________    16   N-Butyl-4-methoxy-2-(methylthio)benzamide                                                         2-Butyl-6-methoxy-1,2-benzisothiazol-3-one                                                       94                                                         (melting point: 50-51° C.)                    17   N-Phenyl-2-methylthio-3-nitrobenzamide                                                            7-Nitro-2-phenyl-1,2-benzisothiazol-3-one                                                        93                                                         (melting point: 152-153° C.)                  18   4-Chloro-2-(methylthio)benzamide                                                                  6-Chloro-1,2-benzisothiazol-3-one                                                                95                                                         (melting point: 271-272° C.)                  19   N-Phenyl-2-(methylthio)benzamide                                                                  2-Phenyl-1,2-benzisothiazol-3-one                                                                81                                                         (melting point: 140-141° C.)                  20   N-Phenyl-2-(methylthio)benzamide                                                                  2-Phenyl-1,2-benzisothiazol-3 one                                                                98                                                         (melting point: 140-141° C.)                  21   2-(Methylthio)benzamide                                                                           1,2-Benzisothiazol-3-one                                                                         97                                                         (melting point: 157-158° C.)                  __________________________________________________________________________     Note *Yield of 1,2Benzisothiazol-3-one against 2(Alkylthio)benzamide.    

The present invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

What is claimed is:
 1. A method for producing an alkylthiobenzamiderepresented by the general formula (III), comprising carrying out areaction of a halobenzamide represented by the following general formula(I): ##STR17## wherein X represents Cl or Br, and R¹ represents ahydrogen atom, or an alkyl group having 1 to 4 carbon atoms, an arylgroup, or an aralkyl group,with an alkanethiol represented by thefollowing general formula (II):

    R.sup.2 SH                                                 (II)

wherein R² represents an alkyl group having 1 to 4 carbon atoms, in thepresence of a base and a phase-transfer catalyst in a heterogeneoussolvent, to give an alkylthiobenzamide represented by the followinggeneral formula (III): ##STR18## wherein R¹ and R² are defined as above.2. The method according to claim 1, wherein the phase-transfer catalystis selected from the group consisting of quaternary ammonium salts andquaternary phosphonium salts.
 3. The method according to claim 1,wherein the compound represented by the general formula (I) is selectedfrom the group consisting of 2-chlorobenzamide,N-ethyl-2-chlorobenzamide, N-phenyl-2-chlorobenzamide,N-4-tolyl-2-chlorobenzamide, N-benzyl-2-chlorobenzamide,2-bromobenzamide, N-ethyl-2-bromobenzamide, N-phenyl-2-bromobenzamide,N-4-tolyl-2-bromobenzamide, N-benzyl-2-bromobenzamide,4-chlorobenzamide, N-ethyl-4-chlorobenzamide,N-phenyl-4-chlorobenzamide, N-4-tolyl-4-chlorobenzamide,N-benzyl-4-chlorobenzamide, 4-bromobenzamide, N-ethyl-4-bromobenzamide,N-phenyl-4-bromobenzamide, N-4-tolyl-4-bromobenzamide, andN-benzyl-4-bromobenzamide.
 4. The method according to claim 1, whereinthe compound represented by the general formula (III) is2-(methylthio)benzamide or N-phenyl-2-(methylthio)benzamide.
 5. Themethod according to claim 1, wherein the base is an alkali metalhydroxide.